BAD/BCL-xL heterodimerization leads to bypass of G0/G1 arrest

Abstract

The pro-apoptotic molecule BAD binds BCL-xL or BCL2 and inactivates their survival function. In addition to their anti-apoptotic function, BCL2 and BCL-xL also delay cell cycle entry from quiescence. We found that the BH3-only molecule BAD also exerted a cell cycle effect. BAD expression resulted in failure to cell cycle block in growth arrest conditions. In low serum and in confluence, fibroblasts constitutively or inducibly expressing BAD persisted in S phase, continued to incorporate BrdU, and exhibited sustained cyclin E/cdk2 activity. Mutation analysis indicated that the cell cycle effect of BAD was not dependent on its phosphorylation status or subcellular localization, but strictly co-segregated with BCL-xL binding, bclx-/- MEFs expressing BAD and bad-/- MEFs both arrested in G0/G1 in low serum similar to wild-type controls, suggesting that the ability to overcome the G0/G1 checkpoint resulted from the presence of BAD/BCL-xL heterodimers, rather than the absence of BCL-xL or BAD. These data provide evidence that in addition to regulating apoptosis, the BAD/BCL-xL heterodimer has a novel cell cycle function.